Memory CD8 T cells derived from nave CD8 T cells after antigenic stimulation are able to mount a more rapid and robust recall immune response than the primary response. Differential expression of the effector molecules and their master regulators provides a key base of memory CD8 T cell functions. How memory CD8 T cells acquire and maintain this differential gene expression is currently unknown. Histone modifications has been recognized as a major player in regulating chromatin states and gene expression yet little is known about their involvement in the function of memory CD8 T cells. We examined three histone modifications (H3K9ac, H3K4me3, H3K27me3) in the gene loci of several effector molecules and their master transcription factors in nave, central (TCM) and effector (TEM) memory CD8 T cells. Gene expressions were positively correlated with the levels of H3K9ac and H3K4me3 and negatively correlated with the levels of H3K27me3 in these gene loci. Furthermore, the patterns and the time of histone modifications in these gene loci differ in the resting and activated nave and memory CD8 T cells, reflecting an additional layer of the regulation corresponding to their function. Finally, reduction of H3K9Ac level resulted in a decrease expression of these differentially expressed genes in memory CD8 T cells. Together, these findings suggest that change of chromatin structure mediated by histone modifications may serve a fundamental basis